Early cryptococcosis infection in a liver transplant patient: A case report

Key Clinical Message In order to early diagnose and prevent the infection dissemination in both suspected solid organ donors and recipients after transplantation, pretransplantation screening tests for rare etiologies like Cryptococcus neoformans should be necessitated, as they can affect many vital organs, especially the brain, liver, and lungs. Abstract Cryptococcosis is a systemic fungal infection mainly affecting immunocompromised patients. The infection is occasionally seen in 16–21 months after organ transplantation, while early involvement is uncommon within <30 days posttransplantation. In the present study, we reported an unusual case of cryptococcosis infection 21 days after transplantation, limited to the transplanted liver in a 60‐year‐old male. Treatment with an antifungal agent showed prompt improvement in his clinical condition.

The most common sites of cryptococcosis in SOT recipients are the central nervous system (CNS), lungs, and skin. In a recent study, up to 5% of SOT recipients with cryptococcosis had a very early infection within less than 30 days posttransplantation, which generally indicates preexisting cryptococcus infection. While two vital organs including the liver and lung are the most common sites for this early infection, involving the former one is with much worse complications. Furthermore, the very early disease is generally found in an unusual site, such as the transplanted allograft or the surgical fossa. Transplanted organ involvement usually suggests transmission from the donor, and it is most common in liver transplants. This finding may be related to the susceptibility of liver transplant recipients to cryptococcosis during transplant candidacy. 8,9 In the present study, we reported a rare and unusual case of a liver transplant in our centers, who presented with liver mass in ultrasonography in his routine follow-up after transplantation. The liver mass biopsy revealed early cryptococcosis infection.

| CASE REPORT
A 60-year-old man, known case of liver cirrhosis due to hepatitis B with orthotopic liver transplantation-from a cadaveric 55-year-old donor with normal routinely checked pretransplant laboratory data who died of a brain stroke-was presented 40 days after transplantation. Tacrolimus (PROGRAF®, Hartkapseln, 1 mg capsule, twice daily), Myfortic (Mycophenolsäure, 360 mg tablet, twice daily), tenofovir (Virbit® 300 mg tablet, daily), and folic acid (Mehrdarou 5 mg tablet, daily) were all being administered to the patient at home. A 20*15 mm welldefined hyper-echogenic lesion was found in the inferior capsule of the right transplanted liver lobe during posttransplant ultrasonography follow-up (21 days later). In order to rule out other possible diagnoses, including autoimmune hepatitis and viral hepatitis, a true cut biopsy was performed under the guidance of a computed tomography (CT). This revealed extensive necrosis containing many fungal elements in favor of cryptococcosis. Cryptococcosis was also detected using the Grocott Methenamine Silver stain (GMS).
His vital sign was steady upon admission to the hospital and no signs of fever were detected. The other part of the physical examination did not reveal any abnormal findings. Detailed laboratory results are shown in Table 1.
Moreover, cytomegalovirus (CMV) and COVID-19 (Corona virus disease-2019) polymerase chain reaction (PCR) were negative. After the consultation with an infectious specialist, liposomal amphotericin B T A B L E 1 Laboratory data of a 60-year-old male presented with cryptococcosis infection 24 days after a liver transplantation. (ExirNano Sina 5 mg/kg/day IV) was started. Moreover, the serum sample for cryptococcus antigen and antibody was taken from the patient and surprisingly were positive, which could imply acute cryptococcosis in the recipient. It is noteworthy that on a review of the recipient's past data, the patient did not have any clinical evidence of any infection. Serum creatinine increased from 1.4 to 2.6 mg/dL during the course of admission. After a week of treatment, amphotericin was switched to fluconazole (AVESINA 800 mg tablet, daily for 4 weeks). Additionally, while in the hospital, he complained of a new onset pulsatile non-migrating headache in the frontal and orbital areas; therefore, the possibility of immune reconstitution inflammatory syndrome (IRIS) and CNS infections was considered. Both a brain CT scan and a paranasal sinus (PNS) CT scan were carried out. The result of the brain CT was completely normal whereas, the PNS CT scan revealed a lesion in the right maxillary sinus. The results of the maxillary sinus and nasal cavity biopsies performed at the ear-nose-throat (ENT) visit were normal. Additionally, the lung CT scan also did not reveal any abnormal findings. After 35 days of treatment initiation, the abdomen-pelvic magnetic resonance imaging (MRI) was completely normal and showed no sign of liver occupying lesion.
Finally, he was discharged in fair condition with oral fluconazole and his other previous medications.

| DISCUSSION
Cryptococcosis is an uncommon infection in the general population that causes serious complications, especially neurologic ones in immune-compromised patients including human immunodeficiency virus (HIV), malignancy, organ transplant, and in cirrhotic patients. Early infection within 30 days posttransplantation is unusual, although this infection occasionally occurs in 16-21 months following organ transplantation. 9,10 According to the Chang et al. report, a 63-year-old lady who had hyperbilirubinemia during her check-up about 2 weeks after transplantation had cryptococcosis found in her liver biopsy. Cryptococcus neoformans was detected in her blood culture as well. 11 We presented a case with liver involvement of cryptococcosis 24 days after a liver transplant. Based on the previous studies, blood group and rhesus (Rh) type, basic metabolic evaluation, complete blood count (CBC) and differential, liver enzyme and coagulating parameters, serum calcium and vitamin D level, urinalysis, urine drug screening, hepatitis A, B, and C serology, HIV, varicella zoster virus (VZV), CMV, Epstein-Barr virus (EBV), rapid plasma reagin (RPR), mumps, measles, rubella, and latent tuberculosis screening were done as routine laboratory tests before liver transplantation. Furthermore, our centers do not routinely assess the pretransplant screening for cryptococcosis. 12 The diagnosis of cryptococcosis in our cases was based on liver lesion biopsy which was incidentally found during posttransplant hepatobiliary ultrasonography. The infection was limited to the transplanted organ and no other organs (lung, skin, brain, etc.) were involved. Besides that, our case's immune-deficiency state was a potential risk factor for early cryptococcal infection. Finally, treatment with an antifungal agent showed prompt improvement in his condition.
According to the report conducted in Brazil in 2020, disseminated cryptococcosis infection was detected in a patient presenting with fever, headache hyponatremia, and elevated aminotransferases enzyme level. Additionally, multiple brain lesions were detected in favor of cryptococcosis in the patient's brain MRI. Disseminated cryptococcosis was also detected in two cases who received a transplanted kidney from the mentioned patient as a donor. 13 It is in contrast with our study as the constitutional symptoms were more prominent in two previous cases rather than in our presented patient.
After candidiasis and aspergillosis, cryptococcosis is the third most common cause of fungal infection among organ-transplanted patients. The primary mechanism of infection in many individuals, particularly in populations with late infection (more than a year after transplant), is the reactivation of latent infection in recipients. Early infection, however, is primarily brought on by a contaminated donor. 11,14,15 It is noteworthy that undiagnosed diseases can be found in donor-derived solid organs. We consider donorderived cryptococcosis to be a differential diagnosis for recipient cryptococcosis, which may result in the same condition in the recipient patient. As a result, it is even more critical to include a cryptococcosis serology test as a routine pretransplant examination for solid organ donors.